Systemic autoimmune diseases (SAID) are complex, chronic, hard to treat, and devastating to patients. Inhalation of asbestos has been shown to increase the risk of SAID such as systemic lupus, and to induce production of a variety of autoantibodies. Autoimmunity occurs when the immune system starts making mistakes and damages our own tissues, and some of this damage is mediated by autoantibodies. While several laboratories across the country are exploring tissue-specific autoantibodies in the pathogenesis of a variety of diseases, this project is unique in exploring a specific set of autoantibodies that are induced by a toxic environmental and occupational exposure: asbestos. This study therefore bridges a gap between toxicology and a specific autoimmune mechanism for asbestos induced lung disease. Performed using a mouse model, this project seeks to a) discover the specific target proteins that the asbestos- induced autoantibodies attack, b) identify the cell signaling pathway(s) that mediate the cellular damage or activation, and c) demonstrate that this damage can happen in a live animal. These discoveries are then directly relevant to development of therapeutic or preventive approaches, by blocking these pathways that lead to damage and disease. PUBLIC HEALTH RELEVANCE: This study, performed in mice, parallels a human study for translational purposes, meaning that what is learned from this study will have direct relevance to our understanding of how autoantibodies to mesothelial cells or fibroblasts can cause damage to lung tissues, and exacerbate the progression of asbestos-induced lung disease. Our ability to understand this process will guide therapeutic and preventive approaches in the future for the relentlessly progressive fibrosis that ultimately leads to death following asbestos exposure.